Introduction to the Compendium on Calcific Aortic Valve Disease
Circulation Research Compendium on Aortic Valve Disease:
Introduction to the Compendium
Introduction to Aortic Stenosis
Hemodynamic and Cellular Response Feedback in Calcific Aortic Valve Disease
Molecular and Cellular Aspects of Calcific Aortic Valve Disease
Fibrocalcific Aortic Valve Disease
Current Management of Calcific Aortic StenosisDonald Heistad & Linda Demer, Editors
Once symptoms arise, stenotic aortic valve disease leads rapidly to death unless surgical or interventional replacement is performed. Already the most prevalent form of valvular heart disease in the Western world, fibrocalcific aortic valve disease affects 25% of those aged >65 years,1 and its incidence is growing inevitably as our population ages. Valve replacement is second only to coronary bypass surgery among operations in the heart. Food and Drug Administration approval of percutaneous transcatheter aortic valve replacement this past year has sparked growing interest in the underlying pathophysiology of the disease. According to many of our textbooks, aortic valve stenosis results from an inevitable, degenerative disorder of aging, due solely to mechanical wear and tear. However, with advances in experimental models and based on pioneering work2–4 by Mohler, Otto, and Rajamannan, recent research findings are now converging on a major shift in paradigm, with inflammation and atherogenic phenomena as the emerging mechanisms.
The goal of this Compendium—the first of its category in Circulation Research—is to update investigators and clinicians on the dramatic changes in our understanding of aortic valve disease through a series of reports covering the spectrum of research, from basic science in valvular interstitial cells, and molecular mechanisms in animal models, to epidemiology of populations and clinical trials in patients.
Carabello5 opens the series with a historical perspective on the new disease of aortic valve stenosis. With rheumatic fever no longer a major cause of aortic stenosis in developed countries, patients now present at older ages, resulting in changes in natural history, clinical signs, and comorbidities. He addresses mechanisms, such as hemodynamic stress and inflammation, which account for the new clinical manifestations. He also comments on the team-based, interventional option, now available for advanced stages of disease, in which a mechanical valve is inserted via a catheter within and, like a stent, expanded over the diseased valve.
In their contribution on hemodynamic and cellular response feedback, Gould, Srigunapalan, Simmons, and Anseth6 report on the mechanically hostile environment facing valves, including shear, bending, tensile, and compressive forces, and how the effects of these stresses depend on the intrinsic mechanical properties of the extracellular matrix. They describe how the growth of calcific nodules on the aortic faces of the cusps in fibrocalcific aortic stenosis depends on the degree to which stress is transferred to the cytoskeleton, which, in turn, depends on extracellular matrix compliance. Based on results from computational, finite element models and ex vivo and in vitro experiments, they describe properties and responses specific to the aortic versus ventricular surfaces of the cusps, paying particular attention to differential endothelial cell adaptation to shear stress, which could account for differences in disease manifestation. They also describe interactions between mechanical events and paracrine signaling, focusing on the role of transforming growth factor-β in modulating normal and pathological responses of valvular interstitial cells.
Towler7 details the molecular and cellular signaling events that promote mineralization and ectopic bone formation in the valve, with an emphasis on similarities to, and distinctions from, bone mineralization; the potential roles of circulating osteoprogenitor cells, morphogens, and endothelial-mesenchymal transformation; the complexity, heterogeneity, and multiple cells involved; as well as spatial and mechanical differences favoring almost exclusive expression of disease on the aortic surface of the cusps. Like Gould et al,6 he makes the intriguing point that the rigid plastic substrate in conventional tissue culture is a better model for the mineralized matrix in calcific aortic valves than for the compliant matrix of normal valves.
In their discussion of mouse models, Weiss et al8 review current techniques for assessing aortic valve function in mice and point out how errors in echocardiography may lead to misdiagnosis of presence and severity of aortic stenosis in this animal model. They emphasize that fibrocalcific changes in the aortic valve may be associated with aortic regurgitation as well as stenosis. They further describe genetic mechanisms that result in bicuspid aortic valves and postnatal predisposition to development of aortic stenosis. They address mechanisms by which oxidative stress, epigenetic modification, inflammation, and angiogenesis may contribute to the pathogenesis of valve disease in the context of aging, hypertension, and genetic causes.
Lindman et al9 incorporate these considerations into state-of-the-art clinical management of aortic stenosis, including risk assessment based on blood tests, calcium mass, and stress testing; explanations for how the classification of severity depends on functional and hemodynamic context; the approach to concomitant hypertension and its effect on left ventricular hypertrophic remodeling, with a focus on the renin–angiotensin system; as well as indications for surgical and percutaneous transcatheter interventions and their limitations in the face of ventricular fibrosis or hypertrophy.
Altogether, this Compendium builds a comprehensive new picture of aortic valve disease, from different expert perspectives all converging on the view that the process is regulated, rather than degenerative, with emerging opportunities for new forms of treatment, intervention, and, potentially, prevention.
Sources of Funding
Original studies of these authors were supported by NIH grants HL16985 (to D.D.H.) and HL114709 (to L.L.D.).
On the Compendium cover: Aortic valve disease in an Ldlr-/-Apob100/100 mouse. α-smooth muscle actin (green), which indicates fibroblast transactivation to myofibroblasts or smooth muscle cell migration, is present throughout the valve. Activated caspase-3 (red), a marker for programmed cell death, is concentrated at sites of valve cusp attachment and in atheroma in aortic annulus. Cell nuclei are stained blue. From: Yi Chu, Robert Weiss, and Donald Heistad.
- © 2013 American Heart Association, Inc.
- Mohler ER 3rd.,
- Gannon F,
- Reynolds C,
- Zimmerman R,
- Keane MG,
- Kaplan FS
- Carabello BA
- Gould ST,
- Srigunapalan S,
- Simmons CA,
- Anseth KS
- Towler DA
- Weiss RM,
- Miller JD,
- Heistad DD
- Lindman BR,
- Bonow RO,
- Otto CM